Topical cyclosporine-containing formulations and uses thereof

ABSTRACT

Provided herein are formulations for topical ophthalmic formulations containing 0.087-0.093 wt % of cyclosporine, and methods of making and using such formulations. In some aspects and embodiments the formulations may include a polyoxyl lipid or fatty acid, and/or a polyalkoxylated alcohol and may include nanomicelles. Also included herein are methods of treating or preventing diseases or conditions, such as ocular diseases or conditions.

FIELD OF THE INVENTION

The present disclosure relates to the field of cyclosporine-containingformulations for topical administration thereof, such as ophthalmicformulations containing 0.087-0.093% of cyclosporine, and methods ofmaking and using such formulations.

BACKGROUND OF THE INVENTION

The information provided herein and references cited are provided solelyto assist the understanding of the reader, and does not constitute anadmission that any of the references or information is prior art to thepresent invention.

United States Patent Application Nos US2010/0310462 and US2009/0092665disclose drug delivery systems for ophthalmic use that have nanomicellesthat include vitamin E TPGS.

Travoprost is an opthalmic solution formulation for reduction ofelevated intraocular pressure in patients with glaucoma or ocularhypertension. It contains 0.5% HCO-40, 0.004% prostaglandin analogtravoprost as active ingredient and propylene glycol as organic solvent.(nlm.nih.gov/dailymed/lookup.cfm?setid=338e7ff4-0d91-4208-a45d-bfa2be52334don the world-wide web). However, this composition is not in the form ofnanomicelles.(ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000665/WC500038389.pdfon the world-wide web).

U.S. Pat. No. 8,980,839 discloses an aqueous ophthalmic solution, saidsolution comprising cyclosporine, a polyoxyl lipid or fatty acid and apolyalkoxylated alcohol. The patent contemplates HCO-40 as polyoxyllipid and Octoxynol-40 as the polyalkoxylated alcohol.

The most common adverse effect following the use of RESTATIS®(cyclosporine 0.05% ophthalmic emulsion) is ocular burning in patientsas reported in 17% cases. Other adverse reactions include conjunctivalhyperemia, epiphora, eye pain, discharge, foreign body sensation,pruritis, stinging and visual disturbance (in 1-5% patients).

SUMMARY OF THE INVENTION

The present disclosure relates to ophthalmic topical formulationscomprising 0.087-0.093 wt % cyclosporine. In certain aspects andembodiments, formulations comprising 0.087-0.093 wt % cyclosporine asdescribed herein do not produce the side effects such as reduced visualacuity, blurred vision, increased lacrimation, eye discharge anddysgeusia as reported in other ophthalmic formulations such as Xiidra®(lifitegrast ophthalmic solution), thus providing a better safetyprofile.

The formulations of the instant disclosure are based, at least in part,on the surprising and unexpected findings that formulations comprising0.087-0.093 wt % cyclosporine can have a higher effectiveness and can beunexpectedly stable, for example, in large scale manufacturing. Featuresand advantages of formulations of the instant disclosure that could nothave been predicted prior to the present disclosure include the improvedhandling thereof upon preparation at industrial scale, i.e., variousaspects and embodiments of formulations of the instant disclosure remainfully fluid in the carrier therefore, and resist the propensity toprecipitate upon handling thereof.

The formulations of the present disclosure in certain embodiments aresurprisingly stable at high temperatures, for example, temperaturesabove about 40 degrees C.

In certain aspects and embodiments, the formulations of the presentdisclosure further include a polyoxyl lipid or fatty acid, and/or apolyalkoxylated alcohol and may include nanomicelles.

Nanomicelles contemplated by the present disclosure typically have aparticle size in the range of about 1-100 nm; in some embodiments, theparticle size falls in the range of about 5-50 nm; in some embodiments,the particle size falls in the range of about 10-40 nm; in someembodiments, the particle size is about 15 nm.

In one aspect, the topical ophthalmic formulations of the presentdisclosure comprise 0.087-0.093 wt % cyclosporine and one or moreadditional formulation ingredients.

In one of the embodiments of the above aspect, formulations contemplatedherein are stable at temperatures above 40 degrees C.

In another embodiment of the above aspect, the formulation of thepresent disclosure is a clear aqueous solution.

In another embodiment of the above aspect, the formulation of thepresent disclosure is substantially free of organic solvents.

In another embodiment of the above aspect, the formulation of thepresent disclosure is free of preservatives.

In another embodiment of the above aspect, the formulation of thepresent disclosure comprises one or more additional formulationingredients.

In another embodiment of the above aspect, the formulation of thepresent disclosure are mixed nanomicellar formulations.

In another embodiment of the above aspect, the formulation of thepresent disclosure comprise cyclosporine encapsulated in core of mixednanomicelles.

In another embodiment of the above aspect, the nanomicelles have aparticle size of about 5-100 nm.

In another embodiment of the above aspect, the formulation of thepresent disclosure comprises one or more additional ingredients.

In another embodiment of the above aspect, the additional ingredientsare selected from the group consisting of a polyoxyl lipid or a fattyacid and a polyalkoxylated alcohol.

In another embodiment of the above aspect, the polyoxyl lipid is apolyoxyl castor oil.

In another embodiment of the above aspect, the polyoxyl lipid isselected from the group consisting of HCO-40, HCO-60, HCO-80 andHCO-100.

In another embodiment of the above aspect, the polyoxyl lipid or fattyacid is present in an amount of about 0.1-5 wt % of the formulation.

In another embodiment of the above aspect, the polyalkoxylated alcoholis octoxynol 40.

In another embodiment of the above aspect, polyalkoxylated alcohol ispresent in an amount of about 0.002-4 wt % of the formulation.

In another embodiment of the above aspect, the formulations of thepresent disclosure comprising additional formulation ingredients arefurther selected from the group consisting of additives, adjuvants,buffers, tonicity agents, bioadhesive polymers and preservatives.

In another embodiment of the above aspect, buffer is selected from thegroup consisting of phosphate, borate, acetate, citrate, carbonate andborate-polyol complexes.

In another embodiment of the above aspect, tonicity agent is selectedfrom the group consisting of mannitol, sodium chloride, sodium nitrate,sodium sulfate, dextrose, xylitol or combinations thereof.

In another embodiment of the above aspect, bioadhesive polymer isselected from the group consisting of carbopol, carbophils, cellulosederivatives, gums such as xanthum, karaya, guar, tragacanth, agarose andother polymers such as povidone, polyethylene glycol, poloxamers,hyaluronic acid or combinations thereof.

In another embodiment of the above aspect, the bioadhesive polymer ispovidone.

In certain aspects and embodiments, the formulations of the presentdisclosure comprise further active agents.

In an embodiment of the above aspect, further active ingredients areselected from the group consisting of resolvin, resolvin-like compounds,steroids, antibiotics, antivirals, hormones, cytokines, toxins, vitaminsor combinations thereof.

In certain aspects and embodiments, the formulations of the presentdisclosure comprise 0.087-0.093 wt % cyclosporine, wherein the saidformulation demonstrates a clinically significant improvement ascompared to the vehicle in tear production with ≥10 mm increase inSchimer test score from baseline.

In an embodiment of the above aspect, the formulations of the presentdisclosure demonstrate an early onset as compared to other formulationsof cyclosporine A.

In certain aspects and embodiments, the formulations of the presentdisclosure comprise:

0.087-0.093 wt % cyclosporine,

about 0.1-6 wt % hydrogenated 40 polyoxyl castor oil, and

about 0.002-4 wt % octoxynol-40.

In certain aspects and embodiments, the formulations of the presentdisclosure comprise:

0.087-0.093 wt % cyclosporine,

about 1.0 wt % hydrogenated 40 polyoxyl castor oil, and

about 0.05 wt % octoxynol-40 (Igepal).

In certain aspects and embodiments, the formulations of the presentdisclosure further comprise:

about 0.20-0.405 wt % sodium phosphate monobasic,

about 0.23-0.465 wt % sodium phosphate dibasic,

about 0.05 wt % sodium chloride,

about 0.3 wt % povidone K90,

sodium hydroxide/hydrochloric acid and

water for injection.

As used herein in connection with numerical values, the terms“approximately” and “about” mean+/−10% of the indicated value, includingthe indicated value.

In some aspects, formulations contemplated herein comprise 0.088-0.093wt % cyclosporine.

In some aspects, formulations contemplated herein comprise 0.089-0.093wt % cyclosporine. In some embodiments of such aspects, the formulationsof the present disclosure comprise:

0.089-0.093 wt % cyclosporine,

about 1.0 wt % hydrogenated 40 polyoxyl castor oil, and

about 0.05 wt % octoxynol-40 (Igepal).

In certain aspects and embodiments, the formulations of the presentdisclosure further comprise:

about 0.20 wt % sodium phosphate monobasic,

about 0.23 wt % sodium phosphate dibasic,

about 0.05 wt % sodium chloride,

about 0.3 wt % povidone K90,

sodium hydroxide/hydrochloric acid and

water for injection.

In some embodiments of such aspects, the formulations of the presentdisclosure comprise:

0.09-0.093 wt % cyclosporine,

about 1.0 wt % hydrogenated 40 polyoxyl castor oil, and

about 0.05 wt % octoxynol-40 (Igepal).

In certain aspects and embodiments, the formulations of the presentdisclosure further comprise:

about 0.405 wt % sodium phosphate monobasic,

about 0.465 wt % sodium phosphate dibasic,

about 0.05 wt % sodium chloride,

about 0.3 wt % povidone K90,

sodium hydroxide/hydrochloric acid and

water for injection.

In some aspects, formulations contemplated herein comprise 0.091-0.093wt % cyclosporine.

In some aspects, formulations contemplated herein comprise 0.092-0.093wt % cyclosporine.

In some aspects, formulations contemplated herein comprise 0.087-0.092wt % cyclosporine.

In some aspects, formulations contemplated herein comprise 0.087-0.091wt % cyclosporine.

In some aspects, formulations contemplated herein comprise 0.087-0.09 wt% cyclosporine. In some embodiments of such aspects, the formulations ofthe present disclosure comprise:

0.087-0.09 wt % cyclosporine,

about 1.0 wt % hydrogenated 40 polyoxyl castor oil, and

about 0.05 wt % octoxynol-40 (Igepal).

In certain aspects and embodiments, the formulations of the presentdisclosure further comprise:

about 0.20 wt % sodium phosphate monobasic,

about 0.23 wt % sodium phosphate dibasic,

about 0.05 wt % sodium chloride,

about 0.3 wt % povidone K90,

sodium hydroxide/hydrochloric acid and

water for injection.

In some embodiments of such aspects, the formulations of the presentdisclosure comprise:

0.087-0.089 wt % cyclosporine,

about 1.0 wt % hydrogenated 40 polyoxyl castor oil, and

about 0.05 wt % octoxynol-40 (Igepal).

In certain aspects and embodiments, the formulations of the presentdisclosure further comprise:

about 0.405 wt % sodium phosphate monobasic,

about 0.465 wt % sodium phosphate dibasic,

about 0.05 wt % sodium chloride,

about 0.3 wt % povidone K90,

sodium hydroxide/hydrochloric acid and

water for injection.

In some aspects, formulations contemplated herein comprise 0.087 wt %cyclosporine.

In some aspects, formulations contemplated herein comprise 0.088 wt %cyclosporine.

In some aspects, formulations contemplated herein comprise 0.089 wt %cyclosporine.

In some aspects, formulations contemplated herein comprise 0.09 wt %cyclosporine.

In some aspects, formulations contemplated herein comprise 0.091 wt %cyclosporine.

In some aspects, formulations contemplated herein comprise 0.092 wt %cyclosporine.

In some aspects, formulations contemplated herein comprise 0.093 wt %cyclosporine.

In certain aspects and embodiments, formulations as described herein areparticularly suitable for anterior eye delivery, or posterior eyedelivery, or anterior and posterior eye delivery.

In certain aspects and embodiments, the formulations of the presentdisclosure consist essentially of:

0.087-0.093 wt % cyclosporine,

about 1.0 wt % hydrogenated 40 polyoxyl castor oil, and

about 0.05 wt % octoxynol-40 (Igepal), and

optionally further consist essentially of:

about 0.20-0.405 wt % sodium phosphate monobasic,

about 0.23-0.465 wt % sodium phosphate dibasic,

about 0.05 wt % sodium chloride,

about 0.3 wt % povidone K90,

NaOH/HCl, and

water for injection.

In some embodiments the formulation has nanomicelles with a relativelyincreased entrapment efficiency; in such embodiments the cyclosporinemay be at least about 0.087%, or at least about 0.088%, or at leastabout 0.089%, or at least about 0.09%, or at least about 0.091%; or atleast about 0.092%; or at least about 0.093%; or no greater than 0.087%;or between 0.087 and 0.093%; or between 0.088 and 0.093%; or between0.089 and 0.093%, or between 0.09 and 0.093%; or about 0.087%, or about0.088%, or about 0.089%; or about 0.09%; or about 0.091%; or about0.092%; or about 0.093%; of the formulation and is present innanomicelles of the formulation.

Accordingly, in one aspect provided is an ophthalmic formulation thatincludes 0.087-0.093 wt % cyclosporine, a polyoxyl lipid or fatty acidand a polyalkoxylated alcohol. In some embodiments the formulationsinclude nanomicelles. In some embodiments the polyoxyl lipid or fattyacid is a polyoxyl castor oil. In some embodiments, the polyoxyl lipidor fatty acid is one or more selected from HCO-40, HCO-60, HCO-80 orHCO-100. In some embodiments the polyoxyl lipid or fatty acid (such as apolyoxyl castor oil such as HCO-40, HCO-60, HCO-80 or HCO-100) ispresent between 0.5 and 5%; or 0.6 and 5%; or 0.7 and 5%; or 0.8 and 5%;or 0.9 and 5%; or 1 and 5%; or 1 and 4%; or 1 and 3%; or 1 and 2%; orabout 1%; or greater than 0.5%; or greater than 0.6%, or greater than0.7%; or greater than 0.8%; or greater than 0.9%; or greater than 1% byweight of the formulation. In some embodiments the polyoxyl lipid isHCO-60. In some embodiments the polyoxyl lipid is HCO-80. In someembodiments the polyoxyl lipid is HCO-100. In some embodiments, theformulation includes a polyalkoxylated alcohol that is octoxynol-40. Insome embodiments, the formulation includes a polyalkoxylated alcohol(such as octoxynol-40) present between 0.01 and 1%; or between 0.02 and1%; or 0.03 and 1%; or 0.04 and 1%; or 0.05 and 1%; or 0.06 and 1%; or0.07 and 1%; or 0.08 and 1%; or about 1% by weight of the formulation.

As used herein, the term “polyoxyl lipid or fatty acid” refers to mono-and diesters of lipids or fatty acids and polyoxyethylene diols.Polyoxyl lipids or fatty acids may be numbered (“n”) according to theaverage polymer length of the oxyethylene units (e.g., 40, 60, 80, 100)as is well understood in the art. The term “n 40 polyoxyl lipid” meansthat the polyoxyl lipid or fatty acid has an average oxyethylene polymerlength equal to or greater than 40 units. Stearate hydrogenated castoroil and castor oil are common lipids/fatty acids commercially availableas polyoxyl lipids or fatty acid, however, it is understood that anylipid or fatty acid could polyoxylated to become a polyoxyl lipid orfatty acid as contemplated herein. Examples of polyoxyl lipid or fattyacids include without limitation HCO-40, HCO-60, HCO-80, HCO-100,polyoxyl 40 stearate, polyoxyl 35 castor oil.

In some embodiments of any of the compositions and methods describedherein, the average polymer length of the oxyethylene units of apolyoxyl lipid or fatty acid is longer for a relatively larger activeingredient and is shorter for a relatively smaller active ingredient;for example in some embodiments in which the active ingredient is aresolvin or resolvin-like compound the polyoxyl lipid is HCO-60 and insome embodiments where the active ingredient is cyclosporine A (which islarger than a resolvin) the polyoxyl lipid is HCO-80 or HCO-100.

As used herein, the term “micelle” or “nanomicelle” refers to anaggregate (or cluster) of surfactant molecules. Micelles only form whenthe concentration of surfactant is greater than the critical micelleconcentration (CMC). Surfactants are chemicals that are amphipathic,which means that they contain both hydrophobic and hydrophilic groups.Micelles can exist in different shapes, including spherical,cylindrical, and discoidal. A micelle comprising at least two differentmolecular species is a mixed micelle. The in some embodiments,ophthalmic compositions of the present disclosure include an aqueous,clear, mixed micellar solution.

In another aspect, provided is an ophthalmic formulation, comprising0.087-0.093 wt % cyclosporine, and a 40 polyoxyl lipid or fatty acid. Insome embodiments the formulations includes nanomicelles. In someembodiments the polyoxyl lipid or fatty acid is a polyoxyl castor oil.In some embodiments, the polyoxyl lipid or fatty acid is one or moreselected from HCO-40, HCO-60, HCO-80 or HCO-100. In some embodiments thepolyoxyl lipid or fatty acid (such as a polyoxyl castor oil such asHCO-40, HCO-60, HCO-80 or HCO-100) is present between 0.1 and 2%, or 0.2and 2%, or 0.3 and 2%; or 0.4 and 2%; or 0.5 and 2%; or 0.6 and 2%; or0.7 and 2%; or 0.8 and 2%; or 0.9 and 2%; or 1 and 2%; or 0.1 and 6%; orabout 4%; or greater than 0.4%; or greater than 1%, or greater than1.5%; or greater than 2%; or greater than 3%; or greater than 4% byweight of the formulation. In some embodiments the polyoxyl lipid isHCO-60. In some embodiments the polyoxyl lipid is HCO-80. In someembodiments the polyoxyl lipid is HCO-100. In some embodiments, theformulation further includes polyalkoxylated alcohol. In someembodiments, the formulation further includes polyalkoxylated alcoholthat is octoxynol-40. In some embodiments, the formulation includes apolyalkoxylated alcohol (such as octoxynol-40) present between 0.002 and4%; or between 0.005 and 3%; or between 0.005 and 2%; or between 0.005and 1%; or between 0.005 and 0.5%; or between 0.005 and 0.1%; or between0.005 and 0.05%; or between 0.008 and 0.02%; or between 0.01 and 0.1%;or between 0.02 and 0.08%; or between 0.005 and 0.08%; or about 0.05%,or about 0.01% by weight of the formulation.

In another aspect, provided is an ophthalmic formulation, that includes0.087-0.093 wt % cyclosporine and a polyoxyl lipid or fatty acid;wherein said polyoxyl lipid or fatty acid is present in an amount equalto or greater than 1% of said formulation. In a similar aspect, providedis an ophthalmic formulation, that includes 0.087-0.093 wt %cyclosporine and a polyoxyl lipid or fatty acid; wherein said polyoxyllipid or fatty acid is present in an amount equal to or greater than0.05% of said formulation. In some embodiments the formulations includesnanomicelles. In some embodiments the polyoxyl lipid or fatty acid is apolyoxyl castor oil. In some embodiments, the polyoxyl lipid or fattyacid is one or more selected from HCO-40, HCO-60, HCO-80 or HCO-100. Insome embodiments the polyoxyl lipid or fatty acid (such as a polyoxylcastor oil such as HCO-60, HCO-80 or HCO-100) is present between 0.5 and2%, or 0.7 and 2%, or between 1 and 6%; or 2 and 6%; or 2 and 6%; or 3and 6%; or 4 and 6%; or 2 and 5%; or 3 and 5%; or 3 and 5%; or 2 and 6%;or about 4%; or greater than 1.5%; or greater than 2%; or greater than3%; or greater than 4% by weight of the formulation. In some embodimentsthe polyoxyl lipid is HCO-40. In some embodiments the polyoxyl lipid isHCO-60. In some embodiments the polyoxyl lipid is HCO-80. In someembodiments the polyoxyl lipid is HCO-100. In some embodiments, theformulation further includes polyalkoxylated alcohol. In someembodiments, the formulation further includes polyalkoxylated alcoholthat is octoxynol-40. In some embodiments, the formulation includes apolyalkoxylated alcohol (such as octoxynol-40) present between 0.002 and4%; or between 0.005 and 3%; or between 0.005 and 2%; or between 0.005and 1%; or between 0.005 and 0.5%; or between 0.005 and 0.1%; or between0.005 and 0.05%; or between 0.008 and 0.02%; or between 0.01 and 0.1%;or between 0.02 and 0.08%; or between 0.005 and 0.08%; or about 0.05%,or about 0.01% by weight of the formulation.

In another aspect, provided is an ophthalmic formulation, that includes0.087-0.093 wt % cyclosporine and a polyoxyl lipid or fatty acid;wherein said formulation comprises nanomicelles. In some embodiments thepolyoxyl lipid or fatty acid is a polyoxyl castor oil. In someembodiments, the polyoxyl lipid or fatty acid is one or more selectedfrom HCO-40, HCO-60, HCO-80 or HCO-100. In some embodiments the polyoxyllipid or fatty acid (such as a polyoxyl castor oil such as HCO-40,HCO-60, HCO-80 or HCO-100) is present between 0.5 and 2%, or 0.7 and 2%,or between 1 and 6%; or 2 and 6%; or 2 and 6%; or 3 and 6%; or 4 and 6%;or 2 and 5%; or 3 and 5%; or 3 and 5%; or 2 and 6%; or about 4%; orgreater than 0.7%; or greater than 1%, or greater than 1.5%; or greaterthan 2%; or greater than 3%; or greater than 4% by weight of theformulation. In some embodiments the polyoxyl lipid is HCO-40. In someembodiments the polyoxyl lipid is HCO-60. In some embodiments thepolyoxyl lipid is HCO-80. In some embodiments the polyoxyl lipid isHCO-100. In some embodiments, the formulation further includespolyalkoxylated alcohol. In some embodiments, the formulation furtherincludes polyalkoxylated alcohol that is octoxynol-40. In someembodiments, the formulation includes a polyalkoxylated alcohol (such asoctoxynol-40) present between 0.002 and 4%; or between 0.005 and 3%; orbetween 0.005 and 2%; or between 0.005 and 1%; or between 0.005 and0.5%; or between 0.005 and 0.1%; or between 0.005 and 0.05%; or between0.008 and 0.02%; or between 0.01 and 0.1%; or between 0.02 and 0.08%; orbetween 0.005 and 0.08%; or about 0.05%, or about 0.01% by weight of theformulation.

In a further aspect provided is an ophthalmic formulation, comprising0.087-0.093 wt % cyclosporine, 1-5% of one or more selected from thegroup consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about0.01-0.05% octoxynol-40.

In another aspect, provided is ophthalmic formulation, comprising0.087-0.093 wt % cyclosporine, 1-5% of one or more selected from thegroup consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about0.01-0.05% octoxynol-40.

In yet another aspect, provided is an ophthalmic formulation, comprising0.087-0.093 wt % cyclosporine, 1-5% of one or more selected from thegroup consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about0.01-0.05% octoxynol-40.

In another aspect, provided is an ophthalmic formulation, comprising0.087-0.093 wt % cyclosporine, 1-5% of one or more selected from thegroup consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about0.01-0.05% octoxynol-40.

In a further aspect provided is an ophthalmic formulation, comprising0.087-0.093 wt % cyclosporine, about 4% of HCO-60 and about 0.01-0.05%octoxynol-40.

In another aspect provided is an ophthalmic formulation, comprising0.087-0.093 wt % cyclosporine, 0.7-1.5% of one or more selected from thegroup consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about0.05-0.1% octoxynol-40.

In another aspect, provided is ophthalmic formulation, comprising0.087-0.093 wt % cyclosporine, 0.7-1.5% of one or more selected from thegroup consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about0.05-0.1% octoxynol-40.

In yet another aspect, provided is an ophthalmic formulation, comprising0.087-0.093 wt % cyclosporine, 0.7-1.5% of one or more selected from thegroup consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about0.05-0.1% octoxynol-40.

In another aspect, provided is an ophthalmic formulation, comprising0.087-0.093 wt % cyclosporine, 0.7-1.5% of one or more selected from thegroup consisting of HCO-40, HCO-60, HCO-80 and HCO-100; and about0.05-0.1% octoxynol-40.

In a further aspect provided is an ophthalmic formulation, comprising0.087-0.093 wt % cyclosporine, about 1% of HCO-60 and about 0.05-0.1%octoxynol-40.

In various embodiments of any of the aspects and embodiments describedherein, the formulation includes nanomicelles.

In some embodiments of the aspects and embodiments described herein, theformulation includes a polyoxyl lipid or fatty acid. In some embodimentsthe polyoxyl lipid or fatty acid is a polyoxyl castor oil. In someembodiments, the polyoxyl lipid or fatty acid is one or more selectedfrom HCO-40, HCO-60, HCO-80 or HCO-100. In some embodiments the polyoxyllipid or fatty acid (such as a polyoxyl castor oil such as HCO-60,HCO-80 or HCO-100) is present between 0.5 and 2%, or 0.7 and 2%, or 1and 6%; or 2 and 6%; or 2 and 6%; or 3 and 6%; or 4 and 6%; or 2 and 5%;or 3 and 5%; or 3 and 5%; or 2 and 6%; or about 4%; or greater than0.7%; or greater than 1%, or greater than 1.5%; or greater than 2%; orgreater than 3%; or greater than 4% by weight of the formulation. Insome embodiments the polyoxyl lipid is HCO-40. In some embodiments thepolyoxyl lipid is HCO-60. In some embodiments the polyoxyl lipid isHCO-80. In some embodiments the polyoxyl lipid is HCO-100.

In some embodiments of the aspects and embodiments disclosed herein,includes a polyalkoxylated alcohol. In some embodiments, the formulationincludes a polyalkoxylated alcohol that is octoxynol-40. In someembodiments, the formulation includes a polyalkoxylated alcohol (such asoctoxynol-40) present between 0.002 and 4%; or between 0.005 and 3%; orbetween 0.005 and 2%; or between 0.005 and 1%; or between 0.005 and0.5%; or between 0.005 and 0.1%; or between 0.005 and 0.05%; or between0.008 and 0.02%; or between 0.01 and 0.1%; or between 0.02 and 0.08%; orbetween 0.005 and 0.08%; or about 0.05%, or about 0.01% by weight of theformulation.

In certain aspects and embodiments, the present disclosure contemplatesstable emulsions comprising:

0.087-0.093 wt % cyclosporine,

about 1.0 wt % hydrogenated 40 polyoxyl castor oil, and

about 0.05 wt % octoxynol-40 (Igepal), and

optionally further comprising:

0.20-0.405 wt % sodium phosphate monobasic,

0.23-0.465 wt % sodium phosphate dibasic,

about 0.05 wt % sodium chloride,

about 0.3 wt % povidone K90,

sodium hydroxide/hydrochloric acid, and

water for injection.

In some aspects, the present disclosure contemplates a process ofpreparing the ophthalmic topical formulation of cyclosporine, saidmethod comprising the steps of:

-   -   (1) melting the required amount of polyoxyl lipid,    -   (2) slowly adding cyclosporine to step (1) and substantially        homogenizing the mixture,    -   (3) adding polyalkoxylated alcohol to step (2) and continue        stirring until a uniform homogeneous solution is obtained,    -   (4) adding buffer system and tonicity agent to the solution        obtained from step (3) and continue stirring to achieve a good        dissolution,    -   (5) adding required amount of bioadhesive polymer to the        solution of above step,    -   (6) adjusting the pH of the solution if required, and making up        the final volume with water for injection; and    -   (7) aseptically filtering and filling the solution into unit        dose vials.

In some aspects, the present disclosure contemplates melt-based methodsfor making cyclosporine-containing formulations, including theabove-described formulations, said methods comprising:

melting hydrogenated 40 polyoxyl castor oil,

slowly adding cyclosporine thereto, and thereafter substantially mixingthe ingredients,

adding octoxynol-40 (Igepal) to the resulting homogeneous mixture andstirring until substantially homogenous, and thereafter

adding this mixture to water for injection, then individually addingexcipients (e.g., sodium phosphate monobasic, sodium phosphate dibasic,and sodium chloride) with stirring sufficient to achieve gooddissolution of each.

An exemplary melt-based manufacturing process contemplated for useherein comprises the following steps:

Step 1: The requisite amount of HCO-40 is melted in a flask heated toabout 60° C. with stirring. When liquefied, the required amount ofcyclosporine is added and mixed until dissolved. The octoxynol-40 isthen added and the entire solution is mixed until uniform.Step 2: The required amount of Water for Injection is charged into astainless steel vessel and stirred until the temperature is 25° C.Step 3: The contents from Step 1 are transferred to the stainless steelvessel and stirred until dissolved.Step 4: The requisite amounts of Sodium Chloride and phosphate bufferare added to the stainless steel vessel, and the contents are mixeduntil dissolved.Step 5: The required amount of Povidone is added to the vessel andstirred till dissolved.Step 6: The pH of the solution in Step 5 is measured, adjusted (ifnecessary) and brought to the final volume with Water for Injection.Step 7: The solution from Step 6 is aseptically filtered and asepticallyfilled into blow/fill/seal (BFS) unit dose vials with a nominal fillvolume of 0.3 mL.Step 8: The vials are packaged in strips of four (4) BFS units in heatsealed foil pouches.

In some aspects, the present disclosure contemplates process ofpreparing the ophthalmic topical formulation of cyclosporine, saidmethod comprising the steps of:

-   -   (1) dissolving the required amounts of cyclosporine,        polyalkoxylated alcohol and polyoxyl lipid in a suitable        solvent,    -   (2) charging the solution obtained from step (1) to a suitable        sized round bottom flask,    -   (3) removing the solvent by rotary evaporation until a thin film        is obtained,    -   (4) adding and mixing required amount of water for injection to        the flask containing film of step (3);    -   (5) adding buffer system and tonicity agent to the solution of        step (4);    -   (6) adding required amount of bioadhesive polymer to the        solution of above step,    -   (7) adjusting the pH of the solution if required, and making up        the final volume with water for injection; and    -   (8) aseptically filtering and filling the solution into unit        dose vials.

An exemplary solvent-based manufacturing process contemplated for useherein comprises the following steps:

-   -   (1) dissolving the required amounts of cyclosporine,        octoxynol-40 and hydrogenated 40 polyoxyl castor oil in a        suitable solvent,    -   (2) charging the solution obtained from step (1) to a suitable        sized round bottom flask,    -   (3) removing the solvent by rotary evaporation until a thin film        is obtained,    -   (4) adding and mixing required amount of water for injection to        the flask containing film of step (3);    -   (5) adding phosphate buffer and sodium chloride to the solution        of step (4);    -   (6) adding required amount of povidone to the solution of above        step,    -   (7) adjusting the pH of the solution if required, and making up        the final volume with water for injection; and    -   (8) aseptically filtering and filling the solution into unit        dose vials.

The instant disclosure further relates to treating or preventing oculardiseases or disorders, for example by local administration of theformulations as described herein.

A patient or subject to be treated by any of the compositions or methodsof the present disclosure can mean either a human or a non-human animal.In an embodiment, the present disclosure provides methods for thetreatment of an ocular disease in a human patient in need thereof. In anembodiment, the present disclosure provides methods for the treatment ofan inflammatory ocular disease in a human patient in need thereof. Inanother embodiment, the present disclosure provides methods for thetreatment of an ocular disease in a veterinary patient in need thereof,including, but not limited to dogs, horses, cats, rabbits, gerbils,hamsters, rodents, birds, aquatic mammals, cattle, pigs, camelids, andother zoological animals.

In some embodiments of the compositions and methods disclosed herein,the cyclosporine further comprises one or more additional activeingredients, e.g., active agents selected from the group consisting of aresolvin or resolvin-like compound, a steroid (such as acorticosteroid), and the like. In some embodiments the additional activeagent includes a resolvin. In some embodiments the additional activeagent includes a corticosteroid. In some embodiments, the additionalactive agent includes a resolvin and a corticosteroid. In someembodiments, the additional active agent includes an antibiotic, forexample one or more antibiotics selected from the group consisting ofazythromycin, ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin,moxifloxacin, besifloxacin, and levofloxacin. In some embodiments, theadditional active agent includes an antibiotic, for example one or moreantibiotics selected from the group consisting of azythromycin,ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin,besifloxacin, and levofloxacin; and a second of such agents is aresolvin such as described herein (including without limitation compound1001). In some embodiments, the active agent includes two or more activeagents and one of said active agents is an antiviral, for example one ormore antivirals selected from the group consisting of ganciclovir,trifluridine, acyclovir, famciclovir, valacyclovir, penciclovir andcidofovir. In some embodiments, the active agent includes two or moreactive agents and one of the active agents is an antibiotic, for exampleone or more antivirals selected from the group consisting ofganciclovir, trifluridine, acyclovir, famciclovir, valacyclovir,penciclovir and cidofovir; and a second of the active agents is aresolvin such as described herein (including without limitation compound1001).

The term “treating” refers to: preventing a disease, disorder orcondition from occurring in a cell, a tissue, a system, animal or humanwhich may be predisposed to the disease, disorder and/or condition buthas not yet been diagnosed as having it; stabilizing a disease, disorderor condition, i.e., arresting its development; and/or relieving one ormore symptoms of the disease, disorder or condition, i.e., causingregression of the disease, disorder and/or condition.

As used herein, a therapeutic that “prevents” a disorder or conditionrefers to a compound that, in a statistical sample, reduces theoccurrence of the disorder or condition in the treated sample relativeto an untreated control sample, or delays the onset or reduces theseverity of one or more symptoms of the disorder or condition relativeto the untreated control sample.

As used herein, the terms “ocular disease,” “ocular condition,” “eyedisease,” and “eye condition” refer to diseases/conditions of the eye(s)that can be sight threatening, lead to eye discomfort, and may signalsystemic health problems.

As used herein, the term “anterior segment disease” refers to alldisorders that affect the eye surface, anterior chamber, iris andciliary body and lens of the eye. The eye surface is composed of thecornea, conjunctiva, eyelids, lacrimal and meibomian glands, and theinterconnecting nerves.

As used herein, the terms “posterior segment eye disease” and“back-of-the-eye disease” refer to all disorders that affect theposterior segment of the eye. A posterior eye disease is a disease whichprimarily affects a posterior ocular site such as choroid or sclera,vitreous, vitreous chamber, retina, optic nerve, and blood vessels andnerves which vascularize or innervate a posterior ocular site.

Accordingly, in another aspect, provided is a method treating orpreventing an ocular disease or condition, that includes locallyadministering a formulation of any of the aspects or embodiments asdisclosed herein. In some embodiments, the ocular disease is an anteriorsegment disease. In some embodiments, the ocular disease is a posteriorsegment disease. In some embodiments, the ocular disease is one or moreselected from the group consisting of dry eye syndrome, Sjogren'ssyndrome, uveitis, anterior uveitis (iritis), chorioretinitis, posterioruveitis, conjunctivitis, allergic conjunctivitis, keratitis,keratoconjunctivitis, vernal keratoconjunctivitis (VKC), atopickeratoconjunctivitis, systemic immune mediated diseases such ascicatrizing conjunctivitis and other autoimmune disorders of the ocularsurface, blepharitis, scleritis, age-related macular degeneration (AMD),diabetic retinopathy (DR), diabetic macular edema (DME), ocularneovascularization, age-related macular degeneration (ARMD),proliferative vitreoretinopathy (PVR), cytomegalovirus (CMV) retinitis,optic neuritis, retrobulbar neuritis, and macular pucker. In oneembodiment, the ocular disease is dry eye. In one embodiment, the oculardisease is allergic conjunctivitis. In one embodiment the ocular diseaseis age-related macular degeneration (AMD). In one embodiment the oculardisease is diabetic retinopathy.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 summarizes the results of the Schirmer Test with vehicle,formulation containing 0.05 wt % cyclosporine and 0.09 wt %cyclosporine.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Active Agents

In accordance various aspects and embodiments of the methods andcompositions provided herein, an active agent, when present in additionto cyclosporine, can be any agent capable of affecting a biologicalprocess. Active agents in addition to cyclosporine (the term activeingredient is used herein interchangably with the term active agent)include drugs, hormones, cytokines, toxins, therapeutic agents, vitaminsand the like. In some embodiments an active agent in accordance with theaspects and embodiments disclosed herein is an agent capable of, orapproved for, treating or preventing an disease or condition, forexample in some embodiments an active agent is capable of, or approvedfor, treating or preventing an ocular disease or condition.

In some embodiments, the active agent in addition to cyclosporine is anantibiotic, for example one or more antibiotics selected from the groupconsisting of azythromycin, ciprofloxacin, ofloxacin, gatifloxacin,levofloxacin, moxifloxacin, besifloxacin, and levofloxacin. In someembodiments, the active agent is an antiviral, for example one or moreantivirals selected from the group consisting of ganciclovir,trifluridine, acyclovir, famciclovir, valacyclovir, penciclovir andcidofovir.

In some embodiments of any of the aspects and embodiments disclosedherein, the active agent is cyclosporine A, an analog thereof, or apharmaceutically acceptable salt thereof.

Cyclosporine, originally extracted from the soil fungus Potypaciadiuminfilatum, has a cyclic 11-amino acid structure and includes e.g.Cyclosporines A through I, such as Cyclosporine A, B, C, D and G.Cyclosporine binds to the cytosolic protein cyclophilin ofimmunocompetent lymphocytes, especially T-lymphocytes, forming acomplex. The complex inhibits calcineurin, which under normalcircumstances induces the transcription of interleukin-2 (IL-2).Cyclosporine also inhibits lymphokine production and interleukinrelease, leading to a reduced function of effector T-cells.

Ocular Diseases

In various aspects and embodiments the formulations as disclosed hereinmay be used to treat or prevent an ocular disease or disorder. Oculardiseases and disorders contemplated herein include anterior segmentdiseases and posterior segment diseases. Exemplary ocular diseases thatmay in certain embodiments be treated with formulations as disclosedherein include the following.

Dry eye syndrome (DES, Chronic dry eye, Keratitis sicca; Xerophthalmia;Keratoconjunctivitis sicca) can be defined as a condition that includesa variety of disorders that result in a loss of, or altered compositionof, the natural tear film, which maintains the surface of the eye.Without this tear film, vision is impaired and patients may suffersevere ocular discomfort. DES can be caused by excessive tearevaporation or by a reduction of tear production in the lacrimal gland,which is the site of tear production. Though the exact causes of thiscondition are unknown, there is evidence supporting the link betweenreduced tear production and inflammation of one or more components ofthe lacrimal apparatus. Currently available medications for DES areleaving substantial room for more effective and better toleratedproducts.

DES may also be a manifestation of Sjogren's syndrome which is anautoimmune disorder in which the glands that produce tears and salivaare destroyed. This leads to dry mouth, decreased tearing, and other drymucous membranes.

Noninfectious uveitis is a chronic inflammatory, putativeTh1/Th17-mediated autoimmune disease associated with substantial visualmorbidity and is potentially blinding. Blindness from uveitis usuallydoes not occur from a single inflammatory episode; rather, cumulativedamage results from recurrent episodes of inflammation. The inflammatorysequelae resulting in vision loss may include one or more of cystoidmacular edema, cataracts, vitreous debris, glaucoma, macular pathology(scarring and atrophy), optic neuropathy, and retinal detachment.

Anterior uveitis (iritis) occurs in the front of the eye and is the mostcommon form of uveitis. Par planitis is an inflammation of the parsplana, a narrow area between the iris and the choroid. This conditionoccurs more frequently in young men, but is usually not associated withanother disease. Posterior uveitis (chondroitis) affects primarily thechoroid; the back portion of the uveal tract. If the retina is alsoinvolved, it is called chorioretinitis. Posterior uveitis may occur inassociation with an autoimmune disease, or follow a systemic infection.In posterior uveitis, inflammation can last from months to years and maycause permanent vision damage, even with treatment.

Uveitis can cause vision impairment, ocular pain, and loss of vision. Itis estimated that about 10% of new cases of blindness in the U.S. arecaused by uveitis. Approximately 300,000 people suffer from uveitis inthe U.S. alone, the majority of whom are affected by anterior uveitis.The only therapeutic class approved by the FDA for treatment of uveitisis corticosteroids, which are noted for multiple side effects, such ashypertension, hyperglycemia, and hypercholesterolemia, and in the eye,glaucoma and cataract formation.

Conjunctivitis (pink eye) describes a group of diseases that causeswelling, itching, burning, and redness of the conjunctiva, theprotective membrane that lines the eyelids and covers exposed areas ofthe sclera, or white of the eye.

Keratitis is an inflammation of the cornea (clear portion in the frontof the eye). Keratitis can be caused by an infection (bacterial, fungal,viral, parasite, etc.) or a non-infectious agent (e.g., certain types ofauto-immune diseases are associated with a variety of non-infectiouskeratitises).

Keratoconjunctivitis refers to an inflammation of the cornea andconjunctiva.

Vernal keratoconjunctivitis (VKC) is a recurrent ocular inflammatorydisease characterized by hard, elevated, cobblestone like bumps on theupper eyelid. There may also be swellings and thickening of theconjunctiva. The conjunctiva is the outermost membrane which lines theeyelids as well as the exposed parts of the eye, except for the cornea.

Atopic keratoconjunctivitis is the result of a condition called atopy.Atopy is a genetic condition whereby the immune system produces higherthan normal antibodies in response to a given allergen.

Systemic immune mediated diseases such as cicatrizing conjunctivitis andother autoimmune disorders of the ocular surface represent a clinicallyheterogeneous group of conditions where acute and chronic autoreactivemechanisms can cause significant damage to the eye. When severe andaffecting the epithelium and substantia propria of the conjunctiva,cicatrization can ensue, leading to significant mechanical alterationsas a result of the fibrosis. These conditions, though generallyinfrequent, can be the cause of profound pathology and visualdisability.

Blepharitis is a common condition that causes inflammation of theeyelids.

Scleritis is a serious inflammatory disease that affects the white outercoating of the eye, known as the sclera.

Age-related macular degeneration (AMD) is a disease associated withaging that gradually destroys sharp, central vision. AMD affects themacula, which is located at the center of the retina. AMD occurs in twoforms: wet and dry. Wet AMD occurs when abnormal blood vessels behindthe retina start to grow under the macula. These new blood vessels tendto be very fragile and often leak blood and fluid. The blood and fluidraise the macula from its normal place at the back of the eye. Damage tothe macula occurs rapidly. Dry AMD occurs when the light-sensitive cellsin the macula slowly break down, gradually blurring central vision inthe affected eye.

Diabetes can affect the eye in a number of ways. Diabetic retinopathy(DR) is a complication of diabetes that results from damage to the bloodvessels of the light-sensitive tissue at the back of the eye (theretina). At first, diabetic retinopathy may cause no symptoms or onlymild vision problems. Eventually, however, diabetic retinopathy canresult in blindness. Diabetic macular edema (DME) is the swelling of theretina in diabetes mellitus due to leaking of fluid from blood vesselswithin the macula.

Ocular neovascularization is the abnormal or excessive formation ofblood vessels in the eye. Ocular neovascularization has been shown indiabetic retinopathy and age-related macular degeneration (AMD).

Proliferative vitreoretinopathy (PVR) is scar tissue formation withinthe eye. “Proliferative” because cells proliferate and“vitreoretinopathy” because the problems involve the vitreous andretina. In PVR scar tissue forms in sheets on the retina which contract.This marked contraction pulls the retina toward the center of the eyeand detaches and distorts the retina severely. PVR can occur bothposteriorly and anteriorly with folding of the retina both anteriorlyand circumferentially.

The cytomegalovirus (CMV) is related to the herpes virus and is presentin almost everyone. When a person's immune system is suppressed becauseof disease (HIV), organ or bone marrow transplant, or chemotherapy, theCMV virus can cause damage and disease to the eye and the rest of thebody. CMV affects the eye in about 30% of the cases by causing damage tothe retina. This is called CMV retinitis.

Optic neuritis occurs when the optic nerve becomes inflamed and themyelin sheath becomes damaged or is destroyed. Nerve damage that occursin the section of the optic nerve located behind the eye, is calledretrobulbar neuritis, which is another term sometimes used for opticneuritis.

Also known as macular pucker, epiretinal membrane is a scar-tissue likemembrane that forms over the macula. It typically progresses slowly andaffects central vision by causing blurring and distortion. As itprogresses, the pulling of the membrane on the macula may causeswelling.

In an embodiment, the compositions can be used for preventing transplantrejection of, for example, corneal allografts following transplantation.It is well known that in inflammation T-lymphocytes play a critical rolein mediating rejection of foreign tissues. Prevention of rejection is ofparamount importance in maintaining the health of transplanted corneas.Rejection may occur in any of the layers comprising the cornea, forexample, the corneal epithelium, the corneal stroma or the cornealendothelium. The functioning of the cornea can be compromised followingendothelial rejection. The endothelial layer serves to maintain thecornea in a compact state, acting as a pump by removing water from thecorneal stroma. If the function of the endothelial layer is compromised,disorientation of collagen fibers can ensue, and transparency of thecornea can be lost. Human endothelial cells are non-replicative, and asa consequence, donor cell loss in the setting of rejection isirreversible and may lead to diminished graft function and survival.Thus, the goal of either prevention or treatment of rejection in cornealtransplant recipients is to minimize endothelial cell loss. Thecompositions of the present disclosure can be used for the prevention ofrejection following corneal allograft transplantation.

Additional Formulation Ingredients

The compositions of the present disclosure may also contain othercomponents such as, but not limited to, additives, adjuvants, buffers,tonicity agents, bioadhesive polymers, and preservatives. In any of thecompositions of this disclosure for topical to the eye, the mixtures arepreferably formulated at about pH 5 to about pH 8. This pH range may beachieved by the addition of buffers to the composition as described inthe examples. In an embodiment, the pH range in the composition in aformulation is about pH 6.6 to about pH 7.0. It should be appreciatedthat the compositions of the present disclosure may be buffered by anycommon buffer system such as phosphate, borate, acetate, citrate,carbonate and borate-polyol complexes, with the pH and osmolalityadjusted in accordance with well-known techniques to properphysiological values. The mixed micellar compositions of the presentdisclosure are stable in buffered aqueous solution. That is, there is noadverse interaction between the buffer and any other component thatwould cause the compositions to be unstable.

Tonicity agents include, for example, mannitol, sodium chloride, sodiumnitrate, sodium sulfate, dextrose, xylitol or combinations thereof.These tonicity agents may be used to adjust the osmolality of thecompositions. In an aspect, the osmolality of the formulation isadjusted to be in the range of about 250 to about 350 mOsmol/kg. In apreferred aspect, the osmolality of the formulation is adjusted tobetween about 280 to about 300 mOsmol/kg.

An additive such as a sugar, a glycerol, and other sugar alcohols, canbe included in the compositions of the present disclosure.Pharmaceutical additives can be added to increase the efficacy orpotency of other ingredients in the composition. For example, apharmaceutical additive can be added to a composition of the presentdisclosure to improve the stability of the calcineurin inhibitor, toadjust the osmolality of the composition, to adjust the viscosity of thecomposition, or for another reason, such as effecting drug delivery.Non-limiting examples of pharmaceutical additives of the presentdisclosure include sugars, such as, trehalose, mannose, D-galactose, andlactose. In an embodiment, the sugars can be incorporated into acomposition prior to hydrating the thin film (i.e. internally). Inanother embodiment, the sugars can be incorporated into a compositionduring the hydration step (i.e. externally). In an embodiment, anaqueous, clear, mixed micellar solution of the present disclosureincludes additives such as sugars.

In an embodiment, compositions of the present disclosure furthercomprise one or more bioadhesive polymers. Bioadhesion refers to theability of certain synthetic and biological macromolecules andhydrocolloids to adhere to biological tissues. Bioadhesion is a complexphenomenon, depending in part upon the properties of polymers,biological tissue, and the surrounding environment. Several factors havebeen found to contribute to a polymer's bioadhesive capacity: thepresence of functional groups able to form hydrogen bridges (—OH, COOH),the presence and strength of anionic charges, sufficient elasticity forthe polymeric chains to interpenetrate the mucous layer, and highmolecular weight. Bioadhesion systems have been used in dentistry,orthopedics, ophthalmology, and in surgical applications. However, therehas recently emerged significant interest in the use of bioadhesivematerials in other areas such as soft tissue-based artificialreplacements, and controlled release systems for local release ofbioactive agents. Such applications include systems for release of drugsin the buccal or nasal cavity, and for intestinal or rectaladministration.

In an embodiment, a composition of the present disclosure includes atleast one bioadhesive polymer. The bioadhesive polymer can enhance theviscosity of the composition and thereby increase residence time in theeye. Bioadhesive polymers of the present disclosure include, forexample, carboxylic polymers like Carbopol® (carbomers), Noveon®(polycarbophils), cellulose derivatives including alkyl and hydroxyalkylcellulose like methylcellulose, hydroxypropylcellulose,carboxymethylcellulose, gums like locust beam, xanthan, agarose, karaya,guar, and other polymers including but not limited to polyvinyl alcohol,povidone, polyethylene glycol, Pluronic® (Poloxamers), tragacanth, andhyaluronic acid; phase-transition polymers for providing sustained andcontrolled delivery of enclosed medicaments to the eye (e.g., alginicacid, carrageenans (e.g., Eucheuma), xanthan and locust bean gummixtures, pectins, cellulose acetate phthalate, alkylhydroxyalkylcellulose and derivatives thereof, hydroxyalkylated polyacrylic acidsand derivatives thereof, poloxamers and their derivatives, etc. Physicalcharacteristics in these polymers can be mediated by changes inenvironmental factors such as ionic strength, pH, or temperature aloneor in combination with other factors. In an embodiment, the optional oneor more bioadhesive polymers is present in the composition from about0.01 wt % to about 10 wt %/volume, preferably from about 0.1 to about 5wt %/volume. In an embodiment, the compositions of the presentdisclosure further comprise at least one hydrophilic polymer excipientselected from, for example, PVP-K-30, PVP-K-90, HPMC, HEC, andpolycarbophil. In an embodiment, the polymer excipient is selected fromPVP-K-90, PVP-K-30 or HPMC. In an embodiment, the polymer excipient isselected from PVP-K-90 or PVP-K-30.

In an embodiment, if a preservative is desired, the compositions mayoptionally be preserved with any of many well-known preservatives,including benzyl alcohol with/without EDTA, benzalkonium chloride,chlorhexidine, Cosmocil® CQ, or Dowicil® 200. In certain embodiments, itmay be desireable for a formulation as described herein to not includeany preservatives. In this regard, preservatives may in some embodimentsnot be necessary or desirable in formulations included in single usecontainers. In other embodiments it may be advantageous to includepreservatives, such as in certain embodiments in which the formulationsare included in a multiuse container.

The ophthalmic compositions can be administered topically to the eye asbiocompatible, aqueous, clear mixed micellar solutions. The compositionshave the drugs incorporated and/or encapsulated in micelles which aredispersed in an aqueous medium.

Non-Limiting List of Exemplary Embodiments

In addition to the aspects and embodiments described and providedelsewhere in this disclosure, the following non-limiting list ofparticular embodiments are specifically contemplated.

1. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,a polyoxyl lipid or fatty acid and a polyalkoxylated alcohol.

2. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,and a n≥40 polyoxyl lipid or fatty acid.

3. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporineand a polyoxyl lipid or fatty acid; wherein said polyoxyl lipid or fattyacid is present in an amount equal to or greater than 0.5% of saidformulation.

4. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporineand a polyoxyl lipid or fatty acid; wherein said formulation comprisesnanomicelles.

5. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,0.5-5% of one or more selected from the group consisting of HCO-40,HCO-60, HCO-80 and HCO-100; and about 0.01-0.1% octoxynol-40.

6. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,0.6-2% of one or more selected from the group consisting of HCO-40,HCO-60, HCO-80 and HCO-100; and about 0.02-0.1% octoxynol-40.

7. An ophthalmic formulation, comprising about 0.09% of cyclosporine,0.5-5% of one or more selected from the group consisting of HCO-40,HCO-60, HCO-80 and HCO-100; and about 0.02-0.1% octoxynol-40.

8. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,0.6-4% of one or more polyoxyl lipids selected from the group consistingof HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.02-0.1% octoxynol-40.

9. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,0.7-4% of polyoxyl lipids or fatty acids; and about 0.02-0.1%octoxynol-40.

10. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,0.8-4% of polyoxyl lipids or fatty acids; and about 0.02-0.1%octoxynol-40; wherein the formulation comprises nanomicelles.

11. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,0.9-4% of polyoxyl lipids or fatty acids; and about 0.02-0.1%octoxynol-40; wherein the formulation comprises nanomicelles.

12. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,about 1% of one or more selected from the group consisting of HCO-40,HCO-60, HCO-80 and HCO-100; and about 0.02-0.1% octoxynol-40.

13. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,about 1% of HCO-60 and about 0.02-0.1% octoxynol-40.

14. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,0.5-4% of one or more selected from the group consisting of HCO-40,HCO-60, HCO-80 and HCO-100; and about 0.05% octoxynol-40.

15. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,0.5-4% of one or more selected from the group consisting of HCO-40,HCO-60, HCO-80 and HCO-100; and about 0.01% octoxynol-40.

16. An ophthalmic formulation, comprising about 0.09% of cyclosporine,0.5-4% of one or more selected from the group consisting of HCO-40,HCO-60, HCO-80 and HCO-100; and about 0.05% octoxynol-40.

17. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,0.6-2% of one or more polyoxyl lipids selected from the group consistingof HCO-40, HCO-60, HCO-80 and HCO-100; and about 0.05% octoxynol-40.

18. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,0.6-2% of polyoxyl lipids or fatty acids; and about 0.05% octoxynol-40.

19. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,0.6-2% of polyoxyl lipids or fatty acids; and about 0.05% octoxynol-40;wherein the formulation comprises nanomicelles.

20. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,0.6-2% of polyoxyl lipids or fatty acids; and about 0.05% octoxynol-40;wherein the formulation comprises nanomicelles.

21. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,about 1% of one or more selected from the group consisting of HCO-40,HCO-60, HCO-80 and HCO-100; and about 0.05% octoxynol-40.

22. An ophthalmic formulation, comprising 0.087-0.093 wt % cyclosporine,about 1% of HCO-60 and about 0.05% octoxynol-40.

23. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.6 and 2% by weight of saidformulation.

24. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.8 and 2% by weight of saidformulation.

25. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.9 and 1.5% by weight of saidformulation.

26. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 1 and 1.5% by weight of saidformulation.

27. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.5 and 5% by weight of saidformulation.

28. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.6 and 5% by weight of saidformulation.

29. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.6 and 4% by weight of saidformulation.

30. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.6 and 3% by weight of saidformulation.

31. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.6 and 2% by weight of saidformulation.

32. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.6 and 1% by weight of saidformulation.

33. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.8 and 5% by weight of saidformulation.

34. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.8 and 4% by weight of saidformulation.

35. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.8 and 3% by weight of saidformulation.

36. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.8 and 2% by weight of saidformulation.

37. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.9 and 2% by weight of saidformulation.

38. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is between 0.9 and 1.5% by weight of saidformulation.

39. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is about 1% by weight of said formulation.

40. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is greater than about 0.6% by weight ofsaid formulation.

41. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is greater than about 0.7% by weight ofsaid formulation.

42. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is greater than about 0.8% by weight ofsaid formulation.

43. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is greater than about 0.9% by weight ofsaid formulation.

44. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is greater than about 1% by weight of saidformulation.

45. The formulation of any of the preceding embodiments, wherein saidpolyalkoxylated alcohol if present is between 0.005 and 4% by weight ofsaid formulation.

46. The formulation of any of the preceding embodiments, wherein saidpolyalkoxylated alcohol if present is between 0.005 and 3% by weight ofsaid formulation.

47. The formulation of any of the preceding embodiments, wherein saidpolyalkoxylated alcohol if present is between 0.005 and 2% by weight ofsaid formulation.

48. The formulation of any of the preceding embodiments, wherein saidpolyalkoxylated alcohol if present is between 0.005 and 1% by weight ofsaid formulation.

49. The formulation of any of the preceding embodiments, wherein saidpolyalkoxylated alcohol if present is between 0.005 and 0.5% by weightof said formulation.

50. The formulation of any of the preceding embodiments, wherein saidpolyalkoxylated alcohol if present is between 0.005 and 0.1% by weightof said formulation.

51. The formulation of any of the preceding embodiments, wherein saidpolyalkoxylated alcohol if present is between 0.005 and 0.05% by weightof said formulation.

52. The formulation of any of the preceding embodiments, wherein saidpolyalkoxylated alcohol if present is between 0.008 and 0.02% by weightof said formulation.

53. The formulation of any of the preceding embodiments, wherein saidpolyalkoxylated alcohol if present is about 0.05% by weight of saidformulation.

54. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is a polyoxyl castor oil.

55. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is one or more selected from HCO-60, HCO-80or HCO-100.

56. The formulation of any of the preceding embodiments, wherein saidpolyoxyl lipid or fatty acid is HCO-60.

57. The formulation of any of the preceding embodiments, wherein saidactive agent comprises a combination of two different agents.

58. The formulation of any of the preceding embodiments, wherein theactive agent comprises two or more active agents selected from the groupconsisting of a resolvin or resolvin-like compound, a steroid (such as acorticosteroid), cyclosporine A, and voclosporin.

59. The formulation of any of the preceding embodiments, wherein theactive agent further comprises a resolvin and a corticosteroid.

60. The formulation of any of the preceding embodiments, wherein theactive agent comprises cyclosporine A and a corticosteroid.

61. The formulation of any of the preceding embodiments, wherein theactive agent comprises a resolvin, cyclosporine A and a corticosteroid.

62. The formulation of any of the preceding embodiments, wherein saidformulation does not include preservatives.

63. The formulation of any of the preceding embodiments, wherein saidformulation does not include benzyl alcohol with/without EDTA,benzalkonium chloride, chlorhexidine, Cosmocil® CQ, or Dowicil® 200.

64. A method of treating or preventing an ocular disease or condition,said method comprising topically administering a formulation of any ofthe preceding embodiments.

65. A method of treating or preventing an ocular disease or condition,said method comprising topically administering a formulation of any ofthe preceding embodiments; wherein said disease is an anterior segmentdisease.

66. A method of treating or preventing an ocular disease or condition,said method comprising topically administering a formulation of any ofthe preceding embodiments; wherein said disease is an posterior segmentdisease.

67. A method of treating or preventing an ocular disease or condition,said method comprising topically administering a formulation of any ofthe preceding embodiments; wherein said disease is one or more selectedfrom the group consisting of dry eye syndrome, Sjogren's syndrome,uveitis, anterior uveitis (iritis), chorioretinitis, posterior uveitis,conjunctivitis, allergic conjunctivitis, keratitis,keratoconjunctivitis, vernal keratoconjunctivitis (VKC), atopickeratoconjunctivitis, systemic immune mediated diseases such ascicatrizing conjunctivitis and other autoimmune disorders of the ocularsurface, blepharitis, scleritis, age-related macular degeneration (AMD),diabetic retinopathy (DR), diabetic macular edema (DME), ocularneovascularization, age-related macular degeneration (ARMD),proliferative vitreoretinopathy (PVR), cytomegalovirus (CMV) retinitis,optic neuritis, retrobulbar neuritis, and macular pucker.

68. A method of treating or preventing an ocular disease or condition,said method comprising topically administering a formulation of any ofthe preceding embodiments; wherein said disease is dry eye syndrome.

69. A method of treating or preventing an ocular disease or condition,said method comprising topically administering a formulation of any ofthe preceding embodiments; wherein said disease is allergicconjunctivitis.

70. A method of treating or preventing an ocular disease or condition,said method comprising topically administering a formulation of any ofthe preceding embodiments; wherein said disease is age-related maculardegeneration (AMD).

The following examples are provided to further illustrate aspects of theinvention. These examples are non-limiting and should not be construedas limiting any aspect of the invention.

Example 1 Preparation of Mixed Nanomicellar Cyclosporine-ContainingFormulations

Mixed nanomicellar formulations cyclosporine are prepared as follows:

-   -   melting hydrogenated 40 polyoxyl castor oil,    -   slowly adding cyclosporine thereto, and thereafter substantially        homogenizing the ingredients,    -   adding octoxynol-40 to the resulting homogeneous mixture and        stirring until substantially homogenous, and thereafter    -   individually adding excipients (e.g., sodium phosphate        monobasic, sodium phosphate dibasic, and sodium chloride) with        stirring sufficient to achieve good dissolution of each.

The prepared formulations are subjected to various tests such asentrapment efficiency, loading efficiency, mixed nanomicellar size andpolydispersity index.

Mixed nanomicellar Size and polydispersity index: The formulation sizeand polydispersity index are determined with Zetasizer, MalvernInstruments, NJ. In brief, approximately 1 ml of each formulation wastransferred to a cuvette and placed in the instrument. A laser beam oflight was used to determine the mixed nanomicellar size. Nanomicellescontemplated by the present disclosure typically have a particle size inthe range of about 1-100 nm; in some embodiments, the particle sizefalls in the range of about 5-50 nm; in some embodiments, the particlesize falls in the range of about 10-40 nm; in some embodiments, theparticle size is about 15 nm.

Entrapment efficiency: To determine the entrapment efficiency of theformulation, all the prepared formulations are subjected to anentrapment efficiency test. Briefly, formulations are vortex mixed forhomogeneity and 1 mL is transferred to a fresh (1.5 mL) eppendorf tube.Each formulation is lyophilized to obtain a solid at the bottom of theeppendorf tube. The obtained solid is suspended in 1 mL of organicsolvent (diethyl ether) to generate reverse micelles and release thedrug into the external organic solvent. The organic solvent isevaporated overnight in speed vacuum. The resultant reversed micellesare resuspended in 1 mL of 2-propanol (dilution factor was taken intoaccount) and further diluted to determine the concentration ofcyclosporine entrapped in each micellar preparation with HPLC. Theentrapment efficiency of the formulation is calculated with thefollowing formula (wherein MNF=Mixed Nanomicellar Formulation):

${{Entrapment}\mspace{14mu} {efficiency}} = {\frac{\left( {{amount}\mspace{14mu} {of}\mspace{14mu} {drug}\mspace{14mu} {quantified}\mspace{14mu} {in}\mspace{14mu} {MNF}} \right)}{{Amount}\mspace{14mu} {of}\mspace{14mu} {drug}\mspace{14mu} {added}\mspace{14mu} {in}\mspace{14mu} {the}\mspace{14mu} {MNF}} \times 100}$

Drug Quantification by an HPLC method: In vitro analysis of cyclosporineis performed by a reversed phase high performance liquid chromatography(RP-HPLC) method with a Shimadzu HPLC pump (Shimadzu, ShimadzuScientific instruments, Columbia, Md.), Alcott autosampler (model 718AL), Shimadzu UV/Visible detector (Shimadzu, SPD-20A/20AV, USA), ODScolumn (5 μm, 150×4.6 mm) thermostated at 40°±1 C and Hewlett PackardHPLC integrator (Hewlett Packard, Palo Alto, Calif.). The mobile phaseis comprised of methanol (MeOH), water and trifluoroacetic acid (TFA)(70:30:0.05% v/v) which is set at a flow rate of 0.5 mL/min. Detectionwavelength is set at 272 nm. The sample tray temperature is maintainedat 4° C. Calibration curve (0.5 to 5 μg/mL) for cyclosporin is preparedby making appropriate dilutions from the stock solution in 2-propanol.An injection volume of 10 μl is injected into the HPLC column foranalysis. All the standards and samples prepared are stored at 4° C.before and during the analysis.

Example 2 Preparation of Mixed Nanomicellar Cyclosporine-ContainingFormulation Using Solvent-Based Method or Melt-Based Method

Mixed nanomicellar formulation encapsulating cyclosporine is prepared bysolvent evaporation method in two steps:

-   -   Compounding of the bulk ophthalmic solution; and    -   Filling of the bulk ophthalmic solution into blow/fill/seal        (BFS) unit doses with subsequent packaging of strips of four (4)        BFS units into individual foil pouches.

An exemplary solvent-based manufacturing process contemplated for useherein is described in more detail as follows:

Step 1: The requisite amounts of cyclosporine, octoxynol-40, and HCO-40are dissolved in ethanol and charged to a suitable size round bottomflask. The flask is attached to a rotary evaporator and rotation isinitiated to mix the contents of the flask.Step 2: The ethanol is removed by rotary evaporation until a thin filmis obtained.Step 3: The requisite amount of Water for Injection is charged to theflask containing the film of Step 2, and the contents are dissolved byrotational (laminar flow) mixing.Step 4: The requisite amounts of Sodium Chloride and previously preparedphosphate buffer are added to a stainless steel vessel, and the contentsare mixed.Step 5: The contents from Step 3 are transferred to the tank containingthe buffer and stirred until dissolved.Step 6: The required amount of Povidone is added to the tank and stirreduntil dissolved.Step 7: The pH of the solution in Step 6 is measured, adjusted (ifnecessary) and brought to the final volume with Water for Injection.Step 8: The solution from Step 7 is aseptically filtered and asepticallyfilled into blow/fill/seal (BFS) unit dose vials with a nominal fillvolume of 0.25 mL.Step 9: The vials are packaged in strips of four (4) BFS units in heatsealed foil pouches.

An exemplary melt-based manufacturing process contemplated for useherein is described in more detail as follows:

Step 1: The requisite amount of HCO-40 is melted in a flask heated toabout 60° C. with stirring. When liquefied, the required amount ofcyclosporine is added and mixed until dissolved. The octoxynol-40 isthen added and the entire solution is mixed until uniform.Step 2: The required amount of Water for Injection is charged into astainless steel vessel and stirred until the temperature is 25° C.Step 3: The contents from Step 1 are transferred to the stainless steelvessel and stirred until dissolved.Step 4: The requisite amounts of Sodium Chloride and phosphate bufferare added to the stainless steel vessel, and the contents are mixeduntil dissolved.Step 5: The required amount of Povidone is added to the vessel andstirred until dissolved.Step 6: The pH of the solution in Step 5 is measured, adjusted (ifnecessary) and brought to the final volume with Water for Injection.Step 7: The solution from Step 6 is aseptically filtered and asepticallyfilled into blow/fill/seal (BFS) unit dose vials with a nominal fillvolume of 0.3 mL.Step 8: The vials are packaged in strips of four (4) BFS units in heatsealed foil pouches.

Example 3 Preparation of Mixed Nanomicellar Cyclosporine-ContainingFormulation Using Ethanol Solvent Evaporation Method

Mixed nanomicellar formulation encapsulating cyclosporin is prepared bysolvent evaporation method in two steps:

Compounding of the bulk ophthalmic solution; and

Filling of the bulk ophthalmic solution into blow/fill/seal (BFS) unitdoses with subsequent packaging of strips of four (4) BFS units intoindividual foil pouches.

The manufacturing process employed herein is described in more detail asfollows:

Step 1: The requisite amounts of cyclosporine, octoxynol-40, and VitaminE Polyethylene Glycol Succinate are dissolved in ethanol and charged toa suitable size round bottom flask. The flask is attached to a rotaryevaporator and rotation is initiated to mix the contents of the flask.Step 2: The ethanol is removed by rotary evaporation until a waxy solidis obtained.Step 3: The requisite amount of Water for Injection is charged to theflask containing the waxy residue in Step 2, and the contents aredissolved by rotational (laminar flow) mixing.Step 4: The contents from Step 3 are transferred to a stainless steelvessel containing the required amount of Povidone solution and thecontents are mixed until uniform.Step 5: The requisite amounts of Sodium Chloride and previously preparedphosphate buffer are added to the solution in Step 4, and the contentsare mixed.Step 6: The pH of the solution in Step 5 is measured, adjusted (ifnecessary) and brought to the final volume with Water for Injection.Step 7: The solution from Step 6 is aseptically filtered and asepticallyfilled into blow/fill/seal (BFS) unit dose vials with a nominal fillvolume of 0.25 mL.Step 8: The vials are packaged in strips of four (4) BFS units in heatsealed foil pouches.

Example 4 Preparation of Mixed Nanomicellar Cyclosporine-ContainingFormulations Using an Alternative Order of Addition Melt-Based Method

Step 1: The requisite amount of HCO-40 is melted in a flask heated toabout 60° C. with stirring. When liquefied, the required amount ofcyclosporine is added and mixed until dissolved and uniform.Step 2: The required amount of Octoxynol-40 is heated to about 60° C.and when liquefied, is added to the cyclosporine HCO-40 mixture.Step 3: The required amount of Water for Injection at about 25° C. ischarged into the flask containing the dissolved cyclosporine and stirreduntil dissolved.Step 4: The requisite amounts of Sodium Chloride and phosphate bufferare added to the flask, and the contents are mixed.Step 5: PVP-K90 is weighed, added to the solution and mixed untildissolved.Step 6: The pH of the solution in Step 5 is measured, adjusted (ifnecessary) and brought to the final volume with Water for Injection.

Example 5

Any of the protocols described herein can be carried out with thefollowing reagents:

0.09 wt % cyclosporine,

1.0 wt % hydrogenated 40 polyoxyl castor oil, and

0.05 wt % octoxynol-40 (Igepal),

0.405 wt % sodium phosphate monobasic, and optionally

0.465 wt % sodium phosphate dibasic,

0.05 wt % sodium chloride,

0.3 wt % povidone K90, and

water for injection.

A randomized, multicenter, double-masked, vehicle-controlled,dose-ranging study was designed to evaluate 2 concentrations of OTX-101ophthalmic solution, 0.09% and 0.05%, against vehicle in approximately420 subjects with keratoconjunctivitis sicca (KCS). Subjects who meteligibility criteria at Screening (patient-reported history of KCS for≥6 months, clinical diagnosis of bilateral KCS, lissamine green stainingscore of ≥3 to ≤9, and global symptom score≥40 based on a modified“Symptom Assessment iN Dry Eye” (SANDE) questionnaire) entered a run-onperiod with vehicle administered topically twice daily (BID) to botheyes for 14 days. Following the run-in, subjects who continued to meetthe lissamine green staining score and global symptom score inclusioncriteria in at least one eye were randomized into 1 of 3 treatmentgroups and received treatment for 12 weeks (84 days):

-   -   OTX-101 0.05% 1 drop in both eyes BID,    -   OTX-101 0.09% 1 drop in both eyes BID, and    -   Vehicle 1 drop in both eyes BID.

Subject symptoms were assessed with the SANDE questionnaire, subjectsigns were assessed with lissamine green conjunctival staining, cornealfluorescein staining, Schirmer's test (unanesthetized), and tearbreak-up time, and subject satisfaction with treatment was assessedusing a 5-point ordinal scale. Safety was assessed by Snellen visualacuity (VA), slit-lamp examination, intraocular pressure (TOP)tonometry, dilated ophthalmoscopy/fundus examination, adverse event (AE)collection, and concomitant medication review. Safety and efficacyevaluations were conducted at study visits on Days 14, 28, 42, 56, and84. Both eyes were assessed at each visit.

The results are presented in FIG. 1, where it can be seen thatformulations according to the present disclosure (containing 0.09 wt %cyclosporine) are substantially more effective than placebo orformulations containing only 0.05 wt % cyclosporine.

Formulations according to the present disclosure containing 0.09 wt %cyclosporine were not only superior to vehicle with respect to theSchirmer's test (p=0.007), such formulations were also superior tovehicle with respect to conjunctival staining (co-primary, p=0.008) andcorneal staining (p<0.001). Formulations of the present disclosure(containing 0.09 wt % cyclosporine) showed clinically meaningfulimprovement in tear production in the subjects with ≥10 mm increase inSchirmer's test score from baseline based on data for both eyes.

The invention illustratively described herein may be practiced in theabsence of any element or elements, limitation or limitations which isnot specifically disclosed herein. The terms and expressions which havebeen employed are used as terms of description and not of limitation,and there is no intention that in the use of such terms and expressionsof excluding any equivalents of the features shown and described orportions thereof, but it is recognized that various modifications arepossible within the scope of the invention claimed. Thus, it should beunderstood that although the present invention has been specificallydisclosed by preferred embodiments and optional features, modificationand variation of the concepts herein disclosed may be resorted to bythose skilled in the art, and that such modifications and variations areconsidered to be within the scope of this invention as defined by theappended claims.

The contents of the articles, patents, and patent applications, and allother documents and electronically available information mentioned orcited herein, are hereby incorporated by reference in their entirety tothe same extent as if each individual publication was specifically andindividually indicated to be incorporated by reference. Applicantsreserve the right to physically incorporate into this application anyand all materials and information from any such articles, patents,patent applications, or other documents.

The inventions illustratively described herein may suitably be practicedin the absence of any element or elements, limitation or limitations,not specifically disclosed herein. Thus, for example, the terms“comprising”, “including,” containing”, etc. shall be read expansivelyand without limitation. Additionally, the terms and expressions employedherein have been used as terms of description and not of limitation, andthere is no intention in the use of such terms and expressions ofexcluding any equivalents of the features shown and described orportions thereof, but it is recognized that various modifications arepossible within the scope of the invention claimed. Thus, it should beunderstood that although the present invention has been specificallydisclosed by preferred embodiments and optional features, modificationand variation of the inventions embodied therein herein disclosed may beresorted to by those skilled in the art, and that such modifications andvariations are considered to be within the scope of this invention.

The invention has been described broadly and generically herein. Each ofthe narrower species and subgeneric groupings falling within the genericdisclosure also form part of the invention. This includes the genericdescription of the invention with a proviso or negative limitationremoving any subject matter from the genus, regardless of whether or notthe excised material is specifically recited herein.

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

Other embodiments are set forth within the following claims.

1.-31. (canceled)
 32. An ophthalmic nanomicellar solution formulationcomprising about 0.087 wt % to about 0.093 wt % encapsulatedcyclosporine, wherein the nanomicelles have a particle size of about 5nm to about 50 nm, and wherein the formulation has a pH of about 5 toabout
 8. 33. The ophthalmic nanomicellar solution formulation of claim32, wherein the formulation has an entrapment efficiency of cyclosporineof about 100%.
 34. The ophthalmic nanomicellar solution formulation ofclaim 32, wherein the formulation is stable at 40° C.
 35. The ophthalmicnanomicellar solution formulation of claim 32, wherein the formulationhas a pH of about 6.6 to about
 7. 36. The ophthalmic nanomicellarsolution formulation of claim 32, wherein the nanomicelles have aparticle size of about 10 nm to about 40 nm.
 37. The ophthalmicnanomicellar solution formulation of claim 32, wherein the nanomicelleshave a particle size of about 15 nm.
 38. The ophthalmic nanomicellarsolution formulation of claim 32, wherein the formulation comprisesabout 0.09 wt % cyclosporine.
 39. A method of increasing tear productionin a subject suffering from keratoconjunctivitis sicca, the methodcomprising topically administering to the eye an ophthalmic nanomicellarsolution formulation twice daily, wherein the formulation comprisesabout 0.087 wt % to about 0.093 wt % encapsulated cyclosporine,nanomicelles particle size of about 5 nm to about 50 nm, and pH of about5 to about
 8. 40. The method of claim 39, wherein the tear production ismeasured by a Schirmer test score from baseline.
 41. The method of claim39, wherein the ophthalmic composition comprises about 0.09 wt %cyclosporine.
 42. The method of claim 39, wherein the formulation has apH of about 6.6 to about
 7. 43. The method of claim 39, wherein thenanomicelles have a particle size of about 10 nm to about 40 nm.
 44. Theophthalmic nanomicellar solution formulation of claim 43, wherein thenanomicelles have a particle size of about 15 nm.
 45. The method ofclaim 39, wherein the ophthalmic composition demonstrates a clinicallysignificant improvement in tear production with >10 mm increase inSchirmer test score from baseline.
 46. A method of treatingkeratoconjunctivitis sicca in a subject, the method comprising topicallyadministering to the eye an ophthalmic nanomicellar solution formulationcomprising about 0.09% wt cyclosporine twice daily, wherein theformulation shows an early onset in clinical improvement compared toother formulations of cyclosporine A.
 47. The method of claim 46,wherein formulation demonstrates clinically significant improvement intear production in tear production with ≥10 mm increase in Schimer testscore from baseline.
 48. The method of claim 46, wherein nanomicelleshave a particle size of about 10 nm to about 40 nm.
 49. The method ofclaim 48, wherein the nanomicelles have a particle size of about 15 nm.50. The method of claim 46, wherein the formulation has a pH of about 5to about
 8. 51. The method of claim 50, wherein the formulation has a pHof about 6.6 to about
 7. 52. A method of treating an anterior ocularcondition, the method comprising administering an ophthalmicnanomicellar solution formulation comprising about 0.087 to about 0.093wt % cyclosporine, wherein the composition has a pH of about 5 to about8, and nanomicelles have a particle size of about 5 nm to about 50 nm.53. The method of claim 52, wherein the anterior ocular condition is dryeye.
 54. The method of claim 52, wherein the ophthalmic nanomicellarsolution formulation is administered twice daily.
 55. The method ofclaim 52, wherein the ophthalmic composition comprises about 0.09 wt %cyclosporine.